Essentially sodium-free effervescent solid pharmaceutical compositions

Abstract

Essentially sodium-free effervescent solid pharmaceutical compositions The present invention relates to an effervescent solid pharmaceutical composition, which is essentially free of sodium content, comprising: a therapeutically effective amount of an active pharmaceutical ingredient; one or more pharmaceutically acceptable alkaline earth metal carbonates or hydrogencarbonates in an amount from 1 to 31% by weight of the composition; and one or more pharmaceutically acceptable acids, pharmaceutically acceptable acid salts, or alternatively, a mixture thereof, in an amount from 2 to 62% by weight of the composition; together with one or more pharmaceutically acceptable excipients or carriers; wherein, the total content of the ion sodium in the effervescent solid pharmaceutical composition is equal to or lower than 1 mmol. It also relates to processes for its preparation and its use in therapy.

Description

[0001]This application claims the benefit of European Patent Application 19382846.4 filed Oct. 2, 2019.[0002]The present invention relates to the field of pharmacy. Particularly, to an effervescent solid pharmaceutical composition which is essentially free of sodium and which has a fast disintegration upon contact with water before its administration. It also relates to processes for its preparation and its use in therapy.BACKGROUND ART[0003]Tablets and capsules are the preferred pharmaceutical forms for the administration of drugs because they are precisely dosed, easily produced on a large scale and contribute to a good compliance with treatment. However, some patients may have trouble in swallowing tablets or capsules. Such condition is particularly important amongst elderly, stroke victims, children, patients affected by psychiatric disorders who refuse to swallow or in general, people who suffer from dysphagia for any other reason.[0004]Liquid dosage forms such as oral solution...

AI Technical Summary

Benefits of technology

The present invention relates to a solid effervescent pharmaceutical composition that does not increase the dietary intake of sodium and alkaline earth metals, while still providing fast effervescence and palatable liquids with no residue. The composition disintegrates quickly in water without leaving any residue and the resulting water solution has a neutral pH value that helps buffer the stomach pH, reducing the risk of drug-induced esophagitis. The composition can also be used for patients who have difficulty swallowing conventional tablets and capsules and provides a more tolerable treatment for patients with dyspepsia, dysphagia, and esophageal ulcers. The composition contains alkaline earth metal carbonates or bicarbonates, which are beneficial for people with special calcium needs and does not exceed the daily upper recommended limit. The low amount of acid / base couple and alkaline earth metal carbonates or bicarbonates used in the composition reduces abrasion during compression, increasing the useful life of tabletting tools. The specific combination of excipients allows for a simple and cost-effective manufacturing process using dry methods, such as direct compression and dry granulation processes. The composition can also be manufactured using a simple wet granulation process.

Problems solved by technology

However, some patients may have trouble in swallowing tablets or capsules.

However, these dosage forms provide a less precise control of the dose since they need to be manipulated by the patient or caregiver; they are more difficult to be transported, and more prone to be contaminated and spoilt, due to the lack of unit-dose packaging.

Unfortunately, these products tend to deliver significant amounts of sodium along with the active pharmaceutical ingredient.

This is particularly important for medications which should be administered chronically, since the cumulative amount of sodium delivered by conventional effervescent solid formulations is unacceptably high for patients with cardiovascular diseases or on low sodium diets.

However, potassium salts are in general less stable than sodium salts, for example potassium bicarbonate decomposes at lower temperatures (between 100 and 200° C.) than sodium bicarbonate (about 270° C.).

Consequently, the use of potassium salts may require special packaging to deal with corrosion and extraordinary precautions of the equipment used.

Therefore, effervescent solid pharmaceutical compositions based on potassium carbonate sources can be difficult to prepare, making them less cost-effective, especially at industrial scale.

Furthermore, it is also disclosed in the state of the art that an excessive dietary intake of potassium could also lead to hyperkalaemia, a condition including symptoms such as muscle weakness, fatigue and arrhythmia among others.

In addition, potassium containing compositions exhibit a metallic and bitter taste which is difficult to mask.

However, getting to much calcium can be harmful causing constipation and might also interfere with the body's ability to absorb iron and zinc.

In adults, too much calcium might increase the risk of kidney stones.

Some studies show that people who consume high amounts of calcium might have increased risks of prostate cancer and heart disease.

Further, calcium can interact or interfere with certain medicines, and some medicines can lower or raise calcium levels in the body.

However, high intakes of magnesium can cause diarrhea, nausea, and abdominal cramping; and extremely high intakes of magnesium can lead to irregular heartbeat and cardiac arrest.

Further, magnesium can also interact or interfere with some medicines such as Bisphosphonates and antibiotics.

Besides, carbonates of alkaline earth metals such as calcium carbonate or magnesium carbonate are sparingly soluble in water and thus, the fast disintegration by effervescence reaction is severely hindered.

Therefore, effervescent compositions comprising alkaline earth metal carbonates are not usually quickly dissolved and as a result, the achieved water mixture after the disintegration of the effervescent composition is neither transparent nor clear leaving residues and / or foams which hinders the bio-absorption of the active ingredient.

Furthermore, the taste of the solutions yielded by these compositions in water is unpleasant, thereby compromising the adherence to treatment.

For these reasons, obtaining effervescent solid pharmaceutical compositions based on alkaline earth metal carbonates or bicarbonates which have a fast disintegration and yield transparent and palatable aqueous solutions is still a challenge.

Even more difficult, having a low amount of alkaline earth metals for avoiding the heathy risks associated to their high intake.

On the other hand, the orally dispersible tablets disclosed in EP1837019 comprise a high percentage of the effervescent couple (i.e. from about 81% to about 94% w / w), and more specifically a high percentage of calcium carbonate (i.e. from about 65% to about 80% w / w), which is disadvantageous because they are extremely abrasive and tend to damage the tabletting tools, thereby causing a severe economic impact in the manufacturing process.

The need of at least two granulation steps, one of them being a wet granulation process makes the effervescent tablets of WO 00 / 28973 more difficult to be produced, hindering at the same time the integrity of the final effervescent tablet and its effervescence time.

Furthermore, as it is mentioned above, the use of high amounts of the effervescent couple and particularly of calcium carbonate are inappropriate because of its abrasiveness that damages the tabletting tools.

Furthermore, although examples 6 to 9 disclose formulations containing lower percentages of the effervescing couple compared to the formulations disclosed in EP 1837019 A1 and WO00 / 28973, the amount of calcium carbonate in the formulations of EP 1067904 is still too high (i.e. higher than 32% w / w), thereby still yielding too abrasive mixtures.